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1.
Phytomedicine ; 93: 153801, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34758437

RESUMO

BACKGROUND: Rheumatoid arthritis (RA) is a common autoimmune disease, for which no economical and safe target drug treatment is available. Chikusetsusaponin Ⅳa (CS-IVa), an active compound in Panax japonicus C.A. Mey, has a good anti-inflammatory effect, but whether this compound can serve as a targeted drug for RA and the corresponding therapeutic mechanism remain unclear. PURPOSE: To investigate the anti-inflammatory and bone-protecting effects of CS-IVa on RA and the possible corresponding mechanisms of action. METHODS: Biomarkers and underlying pathological mechanisms were examined by performing a bioinformatics analysis of RA synovial gene expression data profiles, and the feasibility of CS-IVa treatment for RA was predicted using molecular docking and molecular dynamics simulation techniques. Histomorphological and molecular biology techniques were used to verify the feasibility and molecular mechanism of CS-IVa treatment for RA in vivo using a collagen-induced arthritis (CIA) model. RESULTS: CS-IVa alleviated symptoms and reduced the immune organ index, arthritis index, hind paw thickness, and number of swollen joints in the foot for CIA mice. Bioinformatics analysis suggested that interferon-gamma (IFN-γ), interleukin-1 ß (IL-1ß), and the Janus kinase/signal transduction and activator of transcription (JAK/STAT) pathway played important roles in the pathogenesis of RA. The results of molecular docking and molecular dynamics simulations showed that CS-IVa bound effectively to IFN-γ and IL-1ß and that the combined pose has good stability and flexibility. The histomorphological results showed that CS-IVa reduced joint histopathology scores, OARSI scores, and TRAP-positive cell counts. Molecular biology analysis indicated that CS-IVa reduced the concentration of inflammatory factors in the peripheral serum of CIA mice and suppressed the mRNA expression of these factors in the spleen in a dose-dependent manner. The protein expression level of the JAK/STAT pathway was also inhibited by CS-IVa. CONCLUSION: The results of the current study demonstrate a novel inhibitory effect of CS-IVa on inflammation and bone destruction in CIA mice, and the mechanism may be related to the JAK/STAT signaling pathway, which provides new insights into the development of CS-IVa as a therapeutic agent for RA.


Assuntos
Artrite Experimental , Artrite Reumatoide , Animais , Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Janus Quinases/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Ácido Oleanólico/análogos & derivados , Saponinas , Transdução de Sinais
2.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 37(5): 449-453, 2021 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-34816649

RESUMO

Objective: An animal model of collagen-induced arthritis (CIA) was used to investigate the effects of norepinephrine (NE) and α1-adrenoreceptor (α1-AR) on Treg cells in CIA. Methods: Thirty-two male DBA/1 mice were randomly divided into control group and CIA model group. CIA was prepared by intradermal injection of collagen type II (CII, 100 µl) at the tail base of DBA/1 mice. On the 41th day following primary immunization, co-expression of CD4+T and α1-AR in mouse spleens was observed. Protein expressions of α1-AR in the ankle joints and the spleens of mice were measured by Western blot analysis. The CD4+ T cells were isolated from the mouse spleen tissues in CIA mice and treated with NE or α1-AR agonist phenylephrine. Percentage of Treg cells in mouse CD4+ T cells of CIA mice was determined by flow cytometry. Expressions of α1-AR, transforming growth factor-ß (TGF-ß) and IL-10 in CD4+T cells of CIA mice were assessed by Western blot. Results: Co-expression of CD4 and α1-AR was observed in spleens of both intact and CIA mice. Compared with intace mice, α1-AR expressions in the ankle joints and spleens were down-regulated in CIA mice. NE increased the function of Treg cells in CD4+ T cells of CIA mice compared with that of nothing-treated CD4+T cells of CIA mice. Moreover, the α1-AR agonist phenylephrine increased the Treg cell function in CD4+ T cells of CIA mice relative to that of nothing-treated CD4+T cells of CIA mice. Conclusion: Activating α1-AR on CD4+T cells of CIA mice enhances Treg cell function,facilitating a shift of CD4+T cells toward Treg polarization.


Assuntos
Artrite Experimental , Animais , Colágeno Tipo II , Masculino , Camundongos , Camundongos Endogâmicos DBA , Transdução de Sinais , Linfócitos T Reguladores
3.
Zhongguo Zhen Jiu ; 41(10): 1119-25, 2021 Oct 12.
Artigo em Chinês | MEDLINE | ID: mdl-34628745

RESUMO

OBJECTIVE: To observe the effect of moxibustion at "Zusanli" (ST 36) and "Shenshu" (BL 23) on inflammatory factors and intestinal flora in the rats with adjuvant arthritis. METHODS: A total of 36 Wistar rats were randomized into a normal group, a model group and a moxibustion group, 12 rats in each one. In the model group and the moxibustion group, the adjuvant arthritis model was established by a compound method, including the environmental factors, i.e. wind, cold and damp, and Freund's complete adjuvant. In the moxibustion group, moxibustion intervention was exerted at "Zusanli" (ST 36) and "Shenshu" (BL 23), for 20 min at each acupoint, once daily, consecutively for 21 days. The paw swelling degree and arthritis index (AI) score were observed before and after intervention in the rats of each group. Using real-time fluorescence quantitative PCR method (real-time PCR) and Western blot method, the mRNA and protein expressions of inflammatory factors of colon tissue, i.e. interleukin (IL) 1ß, tumor necrosis factor-α (TNF-α), IL-6, were detected after intervention in the rats of each group. The intestinal flora was detected with 16SrRNA sequencing technology after intervention in the rats of each group. RESULTS: Compared with the normal group, the paw swelling degree and AI score were increased in the rats of the model group (P<0.05); after intervention, compared with the model group, the paw swelling degree and AI score were reduced in the rats of the moxibustion group (P<0.05). Compared with the normal group, the expressions of IL-1ß, TNF-α and IL-6 mRNA, as well as proteins were increased in the colon tissue of the rats in the model group (P<0.05); compared with the model group, the expressions of IL-1ß, TNF-α and IL-6 mRNA, as well as proteins were reduced in the colon tissue of the rats in the moxibustion group (P<0.05). Compared with the normal group, OTUs count was reduced in the rats of the model group (P<0.05); and compared with the model group, OTUs count was increased in the rats of the moxibustion group (P<0.05). Compared with the normal group, Simpson index was increased, Chao1 and Ace were reduced in the rats of the model group (P<0.05); while, compared with the model group, Chao1 and Ace were increased in the rats of the moxibustion group (P<0.05). Compared with the normal group, the relative abundance of uncategorized Clostridium, Lactobacillus, Prevotella, uncategorized Porphyromonadaceae and uncategorized Prevotella was increased (P<0.05), and the relative abundance of uncategorized Spironella was reduced in the model group (P<0.05). While, compared with the model group, the relative abundance of uncategorized Clostridium, Lactobacillus, uncategorized Prevotella was reduced in the moxibustion group (P<0.05) and that of uncategorized Spironella was increased (P<0.05). CONCLUSION: Moxibustion at "Zusanli" (ST 36) and "Shenshu" (BL 23) relieves the joint symptoms of adjuvant arthritis rats and inhibits the expressions of inflammatory factors, which is probably related to the regulation of the structure of intestinal flora.


Assuntos
Artrite Experimental , Artrite Reumatoide , Microbioma Gastrointestinal , Moxibustão , Animais , Artrite Experimental/genética , Artrite Experimental/terapia , Ratos , Ratos Wistar
4.
Arthritis Res Ther ; 23(1): 273, 2021 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-34715926

RESUMO

BACKGROUND: Central nervous system (CNS)-mediated symptoms, such as fatigue, depression, and hyperalgesia, are common complications among patients with rheumatoid arthritis (RA). However, it remains unclear how the peripheral pathology of RA spreads to the brain. Accumulated evidence showing an association between serum cytokine levels and aberrant CNS function suggests that humoral factors participate in this mechanism. In contrast to the well-known early responses of microglia (CNS-resident immune cells) in the area postrema [AP; a brain region lacking a blood-brain barrier (BBB)] to experimental inflammation, microglial alterations in the AP during chronic inflammation like RA remain unclear. Therefore, to determine whether microglia in the AP can react to persistent autoimmune-arthritis conditions, we analyzed these cells in a mouse model of collagen-induced arthritis (CIA). METHODS: Microglial number and morphology were analyzed in the AP of CIA and control mice (administered Freund's adjuvant or saline). Immunostaining for ionized calcium-binding adaptor molecule-1 was performed at various disease phases: "pre-onset" [post-immunization day (PID) 21], "establishment" (PID 35), and "chronic" (PID 56 and 84). Quantitative analyses of microglial number and morphology were performed, with principal component analysis used to classify microglia. Interleukin-1ß (IL-1ß) mRNA expression was analyzed by multiple fluorescent in situ hybridization and real-time polymerase chain reaction. Behavioral changes were assessed by sucrose preference test. RESULTS: Microglia in the AP significantly increased in density and exhibited changes in morphology during the establishment and chronic phases, but not the pre-onset phase. Non-subjective clustering classification of cell morphology (CIA, 1,256 cells; saline, 852 cells) showed that the proportion of highly activated microglia increased in the CIA group during establishment and chronic phases. Moreover, the density of IL-1ß-positive microglia, a hallmark of functional activation, was increased in the AP. Sucrose preferences in CIA mice negatively correlated with IL-1ß expression in brain regions containing the AP. CONCLUSIONS: Our findings demonstrate that microglia in the AP can sustain their activated state during persistent autoimmune arthritis, which suggests that chronic inflammation, such as RA, may affect microglia in brain regions lacking a BBB and have various neural consequences.


Assuntos
Artrite Experimental , Artrite Reumatoide , Animais , Área Postrema , Humanos , Hibridização in Situ Fluorescente , Camundongos , Microglia
5.
Arthritis Res Ther ; 23(1): 265, 2021 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-34696809

RESUMO

BACKGROUND: The development and optimization of therapies for rheumatoid arthritis (RA) is currently hindered by a lack of methods for early non-invasive monitoring of treatment response. Annexin A2, an inflammation-associated protein whose presence and phosphorylation levels are upregulated in RA, represents a potential molecular target for tracking RA treatment response. METHODS: LS301, a near-infrared dye-peptide conjugate that selectively targets tyrosine 23-phosphorylated annexin A2 (pANXA2), was evaluated for its utility in monitoring disease progression, remission, and early response to drug treatment in mouse models of RA by fluorescence imaging. The intraarticular distribution and localization of LS301 relative to pANXA2 was determined by histological and immunohistochemical methods. RESULTS: In mouse models of spontaneous and serum transfer-induced inflammatory arthritis, intravenously administered LS301 showed selective accumulation in regions of joint pathology including paws, ankles, and knees with positive correlation between fluorescent signal and disease severity by clinical scoring. Whole-body near-infrared imaging with LS301 allowed tracking of spontaneous disease remission and the therapeutic response after dexamethasone treatment. Histological analysis showed preferential accumulation of LS301 within the chondrocytes and articular cartilage in arthritic mice, and colocalization was observed between LS301 and pANXA2 in the joint tissue. CONCLUSIONS: We demonstrate that fluorescence imaging with LS301 can be used to monitor the progression, remission, and early response to drug treatment in mouse models of RA. Given the ease of detecting LS301 with portable optical imaging devices, the agent may become a useful early treatment response reporter for arthritis diagnosis and drug evaluation.


Assuntos
Anexina A2 , Artrite Experimental , Artrite Reumatoide , Animais , Artrite Experimental/diagnóstico por imagem , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/tratamento farmacológico , Condrócitos , Camundongos , Imagem Óptica , Tirosina
6.
In Vivo ; 35(6): 3245-3251, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34697155

RESUMO

BACKGROUND/AIM: Using a rat model of collagen-induced arthritis (CIA), we evaluated the therapeutic effects of HM71224 (BTKi), as well as the drug-drug interactions in combined therapy with methotrexate (MTX) based on both drugs' pharmacological role in immune regulation and antiinflammation. MATERIALS AND METHODS: Arthritis in rats was induced using type II collagen and incomplete Freund's adjuvant. The therapeutic effects of HM71224 (alone or in combination with MTX) were evaluated by arthritis score, paw volume, body weight, and histopathological examination (H&E and Safranin-O staining). The drug-drug interactions between HM71224 and MTX were investigated by measuring plasma, liver enzyme and creatinine levels and blood cell counts. RESULTS: HM71224 reduced the clinical signs of arthritis, paw volume, and body weight loss in CIA rats. ED50 and ED90 were 1.0 and 2.5 mg/kg, respectively. HM71224 combined with MTX decreased the arthritis score, bone erosion, synovitis, and cartilage degradation without apparent interaction. CONCLUSION: The combination of HM71224 and MTX improved the therapeutic effect with no drug-drug interactions in RA.


Assuntos
Artrite Experimental , Metotrexato , Animais , Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Quimioterapia Combinada , Metotrexato/farmacologia , Metotrexato/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Ratos
7.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 37(10): 865-871, 2021 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-34670662

RESUMO

Objective To investigate the effects of lncRNA-H19 on fibroblast-like synovial cells(FLS) and collagen induced arthritis (CIA) mice. Methods With FLS isolated and cultured from patients with rheumatoid arthritis (RA), adenovirus, lentivirus and siRNA were used to up-regulate and down-regulate the expression of H19 in RA FLS. BrdU, TranswellTM assay and cell scratch assay were employed to evaluate the proliferation, invasion and migration of RA FLS, respectively. Mice with CIA were locally injected with LV-sh-H19. The progression of CIA was observed by paw thickness, clinical arthritic index, and histologic analysis. Results The expression of H19 was closely associated with the proliferation, invasion and migration of FLS cells and knockdown of H19 significantly ameliorated the progression of CIA in mice. Conclusion H19 is involved in synovial inflammation and progression in CIA mice by promoting the activation of FLS.


Assuntos
Artrite Experimental , RNA Longo não Codificante/metabolismo , Animais , Artrite Experimental/genética , Proliferação de Células , Células Cultivadas , Fibroblastos , Humanos , Inflamação/genética , Camundongos , RNA Longo não Codificante/genética
8.
Stem Cell Res Ther ; 12(1): 535, 2021 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-34627365

RESUMO

BACKGROUND: Tumor necrosis factor (TNF)-α inhibitors represented by Etanercept (a fusion protein containing soluble TNF receptor II (sTNFRII) and the Fc segment of human IgG1) play a pivotal role in Rheumatoid arthritis (RA) treatment. However, long-term use increases the risk of infection and tumors for their systemic inhibition of TNF-α, which disrupts the regular physiological function of this molecular. Mesenchymal stem cells (MSCs)-based delivery system provides new options for RA treatment with their "homing" and immune-regulation capacities, whereas inflammatory environment (especially TNF-α) is not conducive to MSCs' therapeutic effects by inducing apoptosis/autophagy. Here, we constructed a strain of sTNFRII-Fc-expressing MSCs (sTNFRII-MSC), aiming to offset the deficiency of those two interventions. METHODS: Constructed sTNFRII-Fc lentiviral vector was used to infect human umbilical cord-derived MSCs, and sTNFRII-MSC stable cell line was generated by monoclonal cultivation. In vitro and vivo characteristics of sTNFRII-MSC were assessed by coculture assay and an acute inflammatory model in NOD/SCID mice. The sTNFRII-MSC were transplanted into CIA model, pathological and immunological indicators were detected to evaluate the therapeutic effects of sTNFRII-MSC. The distribution of sTNFRII-MSC was determined by immunofluorescence assay. Apoptosis and autophagy were analyzed by flow cytometry, western blot and immunofluorescence. RESULTS: sTNFRII-Fc secreted by sTNFRII-MSC present biological activity both in vitro and vivo. sTNFRII-MSC transplantation effectively alleviates mice collagen-induced arthritis (CIA) via migrating to affected area, protecting articular cartilage destruction, modulating immune balance and sTNFRII-MSC showed prolonged internal retention via resisting apoptosis/autophagy induced by TNF-α. CONCLUSION: sTNFRII-Fc modification protects MSCs against apoptosis/autophagy induced by TNF-α, in addition to releasing sTNFRII-Fc neutralizing TNF-α to block relevant immune-inflammation cascade, and thus exert better therapeutic effects in alleviating inflammatory arthritis.


Assuntos
Artrite Experimental , Transplante de Células-Tronco Mesenquimais , Animais , Apoptose , Autofagia , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Fator de Necrose Tumoral alfa/genética
9.
Sci Rep ; 11(1): 17971, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34504248

RESUMO

Rheumatoid arthritis (RA) is an autoimmune disease associated with advanced joint dysfunction. Madhuca indica J. F. Gmel, from the family Sapotaceae, is an Indian medicinal plant reported to have an array of pharmacological properties. The aim of present investigation was to determine the anti-arthritic potential of an isolated phytoconstituent from methanolic leaf extract of Madhuca indica (MI-ALC) against FCA-induced experimental arthritis. Polyarthritis was induced in female rats (strain: Wistar) via an intradermal injection of FCA (0.1 mL) into the tail. Polyarthritis developed after 32 days of FCA administration. Then rats were treated orally with an isolated phytoconstituent from MI-ALC at doses of 5, 10, and 20 mg/kg. Findings suggested that High-Performance Thin-Layer Chromatography, Fourier-Transform Infrared Spectroscopy, and Liquid Chromatography-Mass Spectrometry spectral analyses of the phytoconstituent isolated from MI-ALC confirmed the structure as 3,5,7,3',4'-Pentahydroxy flavone (i.e., QTN). Treatment with QTN (10 and 20 mg/kg) showed significant (p < 0.05) inhibition of increased joint diameter, paw volume, paw withdrawal threshold, and latency. The elevated synovial oxidative stress (Superoxide dismutase, reduced glutathione, and malondialdehyde) and protein levels of Tumor necrosis factor-α (TNF-α) and Interleukin (ILs) were markedly (p < 0.05) reduced by QTN. It also effectively (p < 0.05) ameliorated cyclooxygenase-2 (COX-2), Nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-kß) and its inhibitor-α (Ikßα), and ATP-activated P2 purinergic receptors (P2X7) protein expressions as determined by western blot analysis. In conclusion, QTN ameliorates FCA-induced hyperalgesia through modulation of elevated inflammatory release (NF-kß, Ikßα, P2X7, and COX-2), oxido-nitrosative stress, and pro-inflammatory cytokines (ILs and TNF-α) in experimental rats.


Assuntos
Antirreumáticos/administração & dosagem , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Flavonoides/administração & dosagem , Madhuca/química , Fitoterapia/métodos , Extratos Vegetais/administração & dosagem , Plantas Medicinais/química , Adjuvantes Imunológicos/efeitos adversos , Administração Oral , Animais , Antirreumáticos/química , Antirreumáticos/isolamento & purificação , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/metabolismo , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Feminino , Flavonoides/química , Flavonoides/isolamento & purificação , Adjuvante de Freund/efeitos adversos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Estrutura Molecular , NF-kappa B/metabolismo , Estresse Nitrosativo/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento
10.
PLoS One ; 16(9): e0257839, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34582486

RESUMO

BACKGROUND: Snail has been linked to the pathogenesis of rheumatoid arthritis (RA). We plan to investigate the regulation of Snail in response to TNF-α, histone acetylation, and glycogen synthase kinase-3 (GSK)-3 inhibition in fibroblast-like synoviocytes (FLSs). METHODS: FLSs from rats with collagen-induced arthritis (CIA) were collected and treated with TNF-α alone or a combination with trichostatin A (TSA), a pan-histone deacetylase inhibitor and lithium chloride (LiCl), a glycogen synthase kinase-3 (GSK)-3 inhibitor. RESULTS: We demonstrated for the first time that nuclear expression of Snail in FLSs from rats with CIA was correlated with the levels of extracellular TNF-α and acetylation status. Cell proliferation and viability of CIA FLSs were reduced in response to TSA treatment and short-hairpin RNA specific to Snail. LiCl treatment increased Snail and cadherin-11 (Cad-11) expression in CIA FLSs. CONCLUSION: We suggested from this study that targeting TNF-α-histone deacetylase-Snail signaling axis or the Wnt signaling pathway in FLSs might provide therapeutic interventions for the treatment of RA in the future.


Assuntos
Artrite Experimental/metabolismo , Ácidos Hidroxâmicos/farmacologia , Cloreto de Lítio/farmacologia , Fatores de Transcrição da Família Snail/metabolismo , Sinoviócitos/citologia , Fator de Necrose Tumoral alfa/farmacologia , Acetilação , Animais , Artrite Experimental/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Ratos , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/metabolismo
11.
Zhen Ci Yan Jiu ; 46(8): 649-55, 2021 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-34472749

RESUMO

OBJECTIVE: To observe the effect of electroacupuncture (EA) of "Zusanli"(ST36) and "Sanyinjiao"(SP6) on serum TNF-α, IL-1ß, and IL-6 and expression of synovial matrimetalloproteinases (MMPs) and articular morphology in collagen-induced arthritis (CIA) rats, so as to explore its mechanisms underlying relief of arthritis. METHODS: Thirty male SD rats were randomly divided into normal control, CIA model and EA groups (n=10 rats per group). The arthritis model was induced by multi-point intradermal injection of bovine type Ⅱ collagen emulsion. EA (2 Hz/100 Hz, 1 mA) was applied to bilateral ST36 and SP6 for 30 min, once a day for 28 days. The hind-limb paw volume was measured and the arthritis index (AI) score given according to the swelling degree, rigidity and deformity of the ankle joint (0-4 points). After EA intervention, the morphological damage of the affected ankle joints was revealed by H.E. staining, safranin O-fast green staining, and tartrate-resistant acid phosphatase (TRAP) staining, separately. The levels of serum TNF-α, IL-1ß, and IL-6 were measured by ELISA, and the expression levels of MMP-1, MMP-3, MMP-13, and receptor activator of nuclear factor Kappa B ligand (RANKL) in the synovial tissue were detected by Western blot. RESULTS: Compared with the normal control group, the paw volume, AI score, TRAP-revealed number of osteoclasts, contents of serum TNF-α, IL-1ß and IL-6, and expression levels of MMP-1, MMP-3, MMP-13 and RANKL proteins were significantly increased in the model group (P<0.01, P<0.05). Following the intervention, the paw volume, AI score, number of osteoclasts, contents of serum TNF- α, IL-1ß and IL-6, and expression levels of MMP-1, MMP-3, MMP-13 and RANKL proteins were significantly decreased in the EA group (P<0.05, P<0.01) in contrast to the model group. H.E. and safranin O-fast green staining showed rough articular cartilage surface with thinned cartilage layer, obvious hyperplasia of the synovial tissue with many inflammatory cells, and serious damage and degradation of the cartilage matrix in the model group, these situations were relatively milder in the EA group. CONCLUSION: EA of ST36 and SP6 can reduce the articular damage in collagen-induced arthritis rats, which is associated with its function in reducing inflammatory response and down-regulating the expression of synovial MMP-1, MMP-3, MMP-13 and RANKL proteins.


Assuntos
Artrite Experimental , Eletroacupuntura , Animais , Artrite Experimental/genética , Artrite Experimental/terapia , Bovinos , Inflamação/genética , Inflamação/terapia , Masculino , Ratos , Ratos Sprague-Dawley , Membrana Sinovial
12.
Biomed Res Int ; 2021: 5574282, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34497850

RESUMO

Programmed cell death 1 ligand (PD-L1) and its receptor (PD-1) are key molecules for immunoregulation and immunotherapy. PD-L1 binding PD-1 is an effective way to regulate T or B cell immunity in autoimmune diseases such as rheumatoid arthritis (RA). In our study, we overexpressed PD-L1 by constructing a recombinant of PD-L1-lentiviral vector, which was subsequently used to transfect mouse bone marrow mesenchymal stem cells (MBMMSCs) and significantly suppressed the development of collagen-induced arthritis (CIA) in DBA/1j mice. In addition, PD-L1-transfected MBMMSCs (PD-L1-MBMMSCs) ameliorated joint damage, reduced proinflammatory cytokine expression, and inhibited T and B cell activation. Furthermore, PD-L1-MBMMSCs decreased the number of dendritic cells and increased the numbers of regulatory T cells and regulatory B cells in joints of CIA mice. In conclusion, our results provided a potential therapeutic strategy for RA treatment with PD-L1-MBMMSC-targeted therapy.


Assuntos
Artrite Experimental/terapia , Artrite Reumatoide/terapia , Antígeno B7-H1/administração & dosagem , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Linfócitos T Reguladores/imunologia , Animais , Artrite Experimental/imunologia , Artrite Experimental/patologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Células Cultivadas , Modelos Animais de Doenças , Ativação Linfocitária , Masculino , Células-Tronco Mesenquimais/imunologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos DBA
13.
J Immunol ; 207(7): 1755-1762, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34470853

RESUMO

Conformation-specific Ags are ideal targets for mAb-based immunotherapy. Here, we demonstrate that the monomeric form of C-reactive protein (mCRP) is a specific therapeutic target for arthritis and nephritis in a murine model. Screening of >1800 anti-mCRP mAb clones identified 3C as a clone recognizing the monomeric, but not polymeric, form of CRP. The anti-mCRP mAb suppressed leukocyte infiltration in thioglycollate-induced peritonitis, attenuated rheumatoid arthritis symptoms in collagen Ab-induced arthritis model mice, and attenuated lupus nephritis symptoms in MRL/Mp-lpr/lpr lupus-prone model mice. These data suggest that the anti-mCRP mAb 3C has therapeutic potential against rheumatoid arthritis and lupus nephritis.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Proteína C-Reativa/imunologia , Imunoterapia/métodos , Nefrite Lúpica/imunologia , Peritonite/imunologia , Pleura/metabolismo , Animais , Anticorpos Monoclonais/metabolismo , Artrite Reumatoide/terapia , Modelos Animais de Doenças , Humanos , Nefrite Lúpica/terapia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Camundongos Endogâmicos MRL lpr , Peritonite/terapia , Ligação Proteica , Conformação Proteica , Isoformas de Proteínas , Toracentese
14.
Zhongguo Zhong Yao Za Zhi ; 46(17): 4504-4510, 2021 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-34581056

RESUMO

In this study, we investigated the mechanism of crude extract of Psammosilene tunicoides(CEPT) in the treatment of rheumatoid arthritis(RA) based on the Nod-like receptor protein 3(NLRP3) inflammasome. The collagen-induced arthritis(CIA) mouse model was established. On day 32 after the primary immunization, according to the arthritis score, the mice were randomly divided into model group, positive control(methotrexate) group, low-and high-dose CEPT groups, and normal group, with 10 mice in each group. According to the administration dose of each group, the mice were continuously administered for 21 days. Every four days during the administration, the paw edema degree, arthritis score, and spleen index of the mice were measured; histopathological examination was performed for the ankles of the mice; the contents of IL-1ß and IL-18 in the serum were determined; the protein expression levels of NLRP3, caspase-1, and apoptosis-associated speck-like protein containing a CARD(ASC), as well as the mRNA expression levels of NLRP3 and caspase-1 in the ankle joints of the mice were detected. The results showed that compared with those in the model group, the mice in the positive control group and CEPT groups had significantly decreased the contents of IL-1ß and IL-18 in the serum and spleen index(P<0.01), significantly lowered arthritis score and degree of paw edema(P<0.01), alleviated arthritic infiltration of the knee, and down-regulated protein and mRNA levels of NLRP3, ASC, and caspase-1 in the ankle joint(P<0.01). These results suggest that P. tunicoides may reduce the paw edema and arthritis score and alleviate the inflammatory response in CIA mice by inhibiting the expression of NLRP3. This study provides a basis for the study of immune regulation of P. tunicoides in RA.


Assuntos
Artrite Experimental , Artrite Reumatoide , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/genética , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Caspase 1/genética , Inflamassomos/genética , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética
15.
J Mech Behav Biomed Mater ; 124: 104719, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34481308

RESUMO

Rheumatoid arthritis (RA) is a systemic polyarticular arthritis that primarily affects the small joints but also causes bone erosion in large joints. None of the currently existing treatment approaches is curable. In this study, the effects of human gingiva-derived mesenchymal stem cells (GMSCs) on collagen-induced arthritis (CIA) mice are examined by experimentally assessing the microstructure and mechanical behaviors of tibia. Bone morphology and mineral density of mouse tibiae were assessed using micro-X-ray computed tomography (micro-CT). Compression testing was performed on mouse tibia to access its stiffness. The deformation and strain localized inside proximal tibia were mapped using mechanical testing coupled with micro-CT and digital volume correlation of micro-CT images. The results show that CIA disease caused bone erosion in epiphyseal cortical bone, which manifested into the adjacent epiphyseal trabecular bone, and also affected the metaphyseal cortical bone. CIA disease also weakened the load-bearing function of proximal tibia. GMSC treatment interfered with the progress of CIA, attenuated the bone erosion in epiphyseal and metaphyseal trabecular bone and resulted in improved load-bearing function of proximal tibia. GMSCs provide a promising potential treatment of autoimmune arthritis.


Assuntos
Artrite Experimental , Células-Tronco Mesenquimais , Animais , Colágeno , Gengiva , Camundongos , Tíbia/diagnóstico por imagem
16.
J Neurosci ; 41(39): 8249-8261, 2021 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-34400519

RESUMO

Pain is the major debilitating symptom of osteoarthritis (OA), which is difficult to treat. In OA patients joint tissue damage only poorly associates with pain, indicating other mechanisms contribute to OA pain. Immune cells regulate the sensory system, but little is known about the involvement of immune cells in OA pain. Here, we report that macrophages accumulate in the dorsal root ganglia (DRG) distant from the site of injury in two rodent models of OA. DRG macrophages acquired an M1-like phenotype, and depletion of DRG macrophages resolved OA pain in male and female mice. Sensory neurons innervating the damaged knee joint shape DRG macrophages into an M1-like phenotype. Persisting OA pain, accumulation of DRG macrophages, and programming of DRG macrophages into an M1-like phenotype were independent of Nav1.8 nociceptors. Inhibition of M1-like macrophages in the DRG by intrathecal injection of an IL4-IL10 fusion protein or M2-like macrophages resolved persistent OA pain. In conclusion, these findings reveal a crucial role for macrophages in maintaining OA pain independent of the joint damage and suggest a new direction to treat OA pain.SIGNIFICANCE STATEMENT In OA patients pain poorly correlates with joint tissue changes indicating mechanisms other than only tissue damage that cause pain in OA. We identified that DRG containing the somata of sensory neurons innervating the damaged knee are infiltrated with macrophages that are shaped into an M1-like phenotype by sensory neurons. We show that these DRG macrophages actively maintain OA pain remotely and independent of joint damage. The phenotype of these macrophages is crucial for a pain-promoting role. Targeting the phenotype of DRG macrophages with either M2-like macrophages or a cytokine fusion protein that skews macrophages into an M2-like phenotype resolves OA pain. Our work reveals a mechanism that contributes to the maintenance of OA pain distant from the affected knee joint and suggests that dorsal root ganglia macrophages are a target to treat osteoarthritis chronic pain.


Assuntos
Artrite Experimental/metabolismo , Gânglios Espinais/metabolismo , Macrófagos/metabolismo , Osteoartrite/metabolismo , Dor/metabolismo , Células Receptoras Sensoriais/metabolismo , Animais , Feminino , Masculino , Camundongos , Nociceptores/fisiologia
17.
J Clin Invest ; 131(18)2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34343136

RESUMO

IL-1ß is a proinflammatory mediator with roles in innate and adaptive immunity. Here we show that IL-1ß contributes to autoimmune arthritis by inducing osteoclastogenic capacity in Tregs. Using mice with joint inflammation arising through deficiency of the IL-1 receptor antagonist (Il1rn-/-), we observed that IL-1ß blockade attenuated disease more effectively in early arthritis than in established arthritis, especially with respect to bone erosion. Protection was accompanied by a reduction in synovial CD4+Foxp3+ Tregs that displayed preserved suppressive capacity and aerobic metabolism but aberrant expression of RANKL and a striking capacity to drive RANKL-dependent osteoclast differentiation. Both Il1rn-/- Tregs and wild-type Tregs differentiated with IL-1ß accelerated bone erosion upon adoptive transfer. Human Tregs exhibited analogous differentiation, and corresponding RANKLhiFoxp3+ T cells could be identified in rheumatoid arthritis synovial tissue. Together, these findings identify IL-1ß-induced osteoclastogenic Tregs as a contributor to bone erosion in arthritis.


Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Interleucina-1beta/imunologia , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Artrite Experimental/etiologia , Artrite Experimental/patologia , Artrite Reumatoide/etiologia , Artrite Reumatoide/patologia , Diferenciação Celular/imunologia , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/deficiência , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Osteoclastos/imunologia , Osteoclastos/patologia , Osteogênese/imunologia , Ligante RANK/imunologia , Linfócitos T Reguladores/metabolismo
18.
Immunology ; 164(3): 617-636, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34351636

RESUMO

Proper regulation of B-cell function is essential for effective humoral immunity and maintenance of immune tolerance. Here, we found that FBW7 (F-box/WD40 repeat-containing protein 7) is highly expressed in germinal centre B and B1 cells, and confirmed that it has an intrinsic role in maintaining homeostasis of mature B cells and B-1 cells. FBW7 deletion led to an impairment of antibody response, and although germinal centre formation was not affected, antibody class-switch recombination and affinity maturation processes were defective. Likewise, memory immune response was severely impaired. Moreover, FBW7 ablation ameliorated the pathogenesis of an autoimmune disease model, collagen-induced arthritis, by reducing the production of anti-collagen II autoantibodies. Taken together, these data suggest that FBW7 may be an attractive target for developing new therapeutics for the treatment of autoimmune diseases.


Assuntos
Artrite Experimental/imunologia , Linfócitos B/imunologia , Proteína 7 com Repetições F-Box-WD/metabolismo , Animais , Artrite Experimental/diagnóstico , Artrite Experimental/patologia , Linfócitos B/metabolismo , Colágeno/administração & dosagem , Colágeno/imunologia , Proteína 7 com Repetições F-Box-WD/genética , Feminino , Centro Germinativo/citologia , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Humanos , Switching de Imunoglobulina/genética , Memória Imunológica , Masculino , Camundongos , Camundongos Knockout , Índice de Gravidade de Doença , Ubiquitinação/imunologia
19.
Sci Rep ; 11(1): 17312, 2021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-34453072

RESUMO

Resolvins, are specialized pro-resolving mediators (SPMs) derived from n-3 polyunsaturated fatty acids. They contribute actively to the resolution of inflammation, but little is known concerning their role in chronic inflammation, such as in rheumatoid arthritis (RA). Here, we performed lipid mediator (LM) profiling in tissues from the paws of SKG arthritic mice using lipid chromatography (LC)/mass spectrometry (MS)/MS-based LM metabololipidomics. We found elevated levels of SPMs including resolvin D5 (RvD5) in these tissues. Moreover, RvD5 levels were significantly correlated with arthritis disease activity. From experiments to assess the role of RvD5 in the pathology of RA, we concluded that RvD5 suppressed Th17 cell differentiation and facilitated regulatory T cell differentiation, as well as inhibiting CD4+ T cell proliferation. Furthermore, RvD5 attenuated osteoclast differentiation and interfered with osteoclastogenesis. Targeting the resolution of inflammation could be promising as a novel treatment for RA.


Assuntos
Artrite Reumatoide/fisiopatologia , Ácidos Docosa-Hexaenoicos/metabolismo , Osteogênese/fisiologia , Células Th17/metabolismo , Zimosan/farmacologia , Animais , Artrite Experimental , Diferenciação Celular , Proliferação de Células , Cromatografia Líquida de Alta Pressão , , Humanos , Inflamação , Camundongos , Espectrometria de Massas em Tandem
20.
PLoS One ; 16(8): e0250910, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34398899

RESUMO

INTRODUCTION: Periprosthetic joint infection (PJI) represents a devastating complication of total joint arthroplasty associated with significant morbidity and mortality. Literature suggests a possible higher incidence of periprosthetic joint infection (PJI) in patients with rheumatoid arthritis (RA). There is, however, no consensus on this purported risk nor a well-defined mechanism. This study investigates how collagen-induced arthritis (CIA), a validated animal model of RA, impacts infectious burden in a well-established model of PJI. METHODS: Control mice were compared against CIA mice. Whole blood samples were collected to quantify systemic IgG levels via ELISA. Ex vivo respiratory burst function was measured via dihydrorhodamine assay. Ex vivo Staphylococcus aureus Xen36 burden was measured directly via colony forming unit (CFU) counts and crystal violet assay to assess biofilm formation. In vivo, surgical placement of a titanium implant through the knee joint and inoculation with S. aureus Xen36 was performed. Bacterial burden was then quantified by longitudinal bioluminescent imaging. RESULTS: Mice with CIA demonstrated significantly higher levels of systemic IgG compared with control mice (p = 0.003). Ex vivo, there was no significant difference in respiratory burst function (p = 0.89) or S. aureus bacterial burden as measured by CFU counts (p = 0.91) and crystal violet assay (p = 0.96). In vivo, no significant difference in bacterial bioluminescence between groups was found at all postoperative time points. CFU counts of both the implant and the peri-implant tissue were not significantly different between groups (p = 0.82 and 0.80, respectively). CONCLUSION: This study demonstrated no significant difference in S. aureus infectious burden between mice with CIA and control mice. These results suggest that untreated, active RA may not represent a significant intrinsic risk factor for PJI, however further mechanistic translational and clinical studies are warranted.


Assuntos
Artrite Experimental , Artroplastia do Joelho , Interface Osso-Implante , Articulação do Joelho , Prótese do Joelho/microbiologia , Infecções Estafilocócicas , Staphylococcus aureus/metabolismo , Animais , Artrite Experimental/metabolismo , Artrite Experimental/microbiologia , Artrite Experimental/patologia , Carga Bacteriana , Interface Osso-Implante/microbiologia , Interface Osso-Implante/patologia , Articulação do Joelho/metabolismo , Articulação do Joelho/microbiologia , Articulação do Joelho/patologia , Articulação do Joelho/cirurgia , Masculino , Camundongos , Fatores de Risco , Infecções Estafilocócicas/metabolismo , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/patologia
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